Amoxicillin + clavulanic acid

Amoxicillin + clavulanic acid is an Antibiotic belonging to the Penicillin Derivatives /Beta-lactamase inhibitors.

The combination of amoxicillin and clavulanic acid is used to treat certain infections caused by bacteria, including infections of the ears, lungs, sinus, skin, and urinary tract. Amoxicillin is in a class of medications called penicillin-like antibiotics. It works by stopping the growth of bacteria. Clavulanic acid is in a class of medications called beta-lactamase inhibitors.

Amoxicillin: It is rapidly and well absorbed from the gastrointestinal tract. Increased absorption and decreased gastrointestinal upset with food. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1-2 hours. Via IV, Amoxicillin readily distributed into body tissues and fluids (e.g. gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus) except the brain and CSF. It crosses placenta and enters breast milk. The Volume of distribution is approximately 0.3-0.4 L/kg. The Plasma protein binding is approximately 18%. It is Metabolised to a limited extent to form inactive penicilloic acid. Amoxicillin: It is excreted mainly via urine (approx 60-80% as unchanged drug). The Elimination half-life is approximately 1.3 hours.

Clavulanic acid: It is rapidly and well absorbed from the gastrointestinal tract. Decreased absorption with high-fat meals. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1.5 hours. Via IV, Clavulanic acid is well distributed into body tissues and fluids (e.g., gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus). Crosses placenta and enters breast milk. Volume of distribution: Approx 0.2 L/kg. Plasma protein binding: Approx 25%. It is extensively metabolised. It is excreted via urine (approx 25-40% as unchanged drug); faeces; expired air. The Elimination half-life is approximately 1 hour.

Amoxicillin + clavulanic acid shows common side effects like Diarrhea, upset stomach, vomiting, mild skin rash.

Amoxicillin + clavulanic acid is available in the form of Oral Tablet and Reconstituted Suspension.

Amoxicillin + clavulanic acid is available in India, US, UK, Singapore, Italy, France, Spain, Canada, China, Japan and Australia.

Amoxicillin + clavulanic acid belonging to the Penicillin Derivatives /Beta-lactamase inhibitors, acts as an Antibiotic.

Clavulanic acid binds and inhibits beta-lactamases that inactivate amoxicillin resulting in amoxicillin having an expanded spectrum of activity. Amoxicillin inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

The Data of onset of action of Amoxicillin + clavulanic acid is not available.

The Tmax of Amoxicillin + clavulanic acid is found to be approximately 1-2 hours (Amoxicillin) and 1.5 hours (clavulanic acid).

The Data of duration of Action of Amoxicillin + clavulanic acid is not available.

Amoxicillin + clavulanic acid is available in the form of Oral Tablet and Reconstituted Suspension.

Amoxicillin + clavulanic acid Tablet and Reconstituted Suspension is taken orally.

The combination of amoxicillin and clavulanic acid is used to treat certain infections caused by bacteria, including infections of the ears, lungs, sinus, skin, and urinary tract. Amoxicillin is in a class of medications called penicillin-like antibiotics. It works by stopping the growth of bacteria. Clavulanic acid is in a class of medications called beta-lactamase inhibitors. It works by preventing bacteria from destroying amoxicillin.

Amoxicillin + clavulanic acid is an Antibiotic belonging to the Penicillin Derivatives /Beta-lactamase inhibitors.

Amoxicillin + clavulanic acid is approved for use in the following clinical indications

Adult indication

• Bite wound infection, prophylaxis or treatment
• Chronic obstructive pulmonary disease, acute exacerbation
• Diabetic foot infection
• Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure
• Neutropenic fever, low-risk cancer patients
• Odontogenic infection
• Otitis media, acute
• Peritonsillar cellulitis or abscess
• Pneumonia
• Rhinosinusitis, acute bacterial
• Streptococcus, chronic carriage
• Urinary tract infection

Pediatric indication

• Impetigo
• Otitis media, acute
• Pneumonia, community-acquired
• Rhinosinusitis, acute bacterial
• Streptococcus, group A; chronic carriage
• Urinary tract infections

Adult Dose

• Bite wound infection, prophylaxis or treatment

Oral: Immediate release: 875 mg every 12 hours.

• Chronic obstructive pulmonary disease, acute exacerbation

Oral: Immediate release: 500 mg every 8 hours or 875 mg every 12 hours for 5 to 7 days.

• Diabetic foot infection

Oral: Immediate release: 875 mg every 12 hours. Duration of therapy should be tailored to individual clinical circumstances; most patients with infection limited to skin and soft tissue respond to 1 to 2 weeks of therapy.

• Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure

Immediate release: Oral: 875 mg every 8 hours.

Extended release: Oral: 2 g every 12 hours.

• Neutropenic fever, low-risk cancer patients

Oral: Immediate release: 500 mg every 8 hours or 875 mg every 12 hours. Combine either dosing regimen with oral ciprofloxacin; continue until resolution of fever and neutropenia.

• Odontogenic infection

Oral: Immediate release: 875 mg every 12 hours or 500 mg every 8 hours for 5 to 7 days.

• Otitis media, acute

Immediate release: 875 mg twice daily or 500 mg every 8 hours.

Extended release: 1 or 2 g twice daily, based on weight and severity of infection; some experts prefer the extended-release formulation for patients at high risk of severe infection or resistant S. pneumoniae.

Duration: 5 to 7 days for mild to moderate infection and 10 days for severe infection.

• Peritonsillar cellulitis or abscess

Oral: Immediate release: 875 mg every 12 hours to complete a total of 14 days of therapy.

• Pneumonia

Aspiration pneumonia (community acquired [mild]):

Immediate release: Oral: 875 mg twice daily.

Extended release: Oral: 2 g twice daily.

Duration of therapy: Generally 5 days.

Community-acquired pneumonia:

Immediate release: Oral: 500 mg 3 times daily or 875 mg twice daily as part of an appropriate combination regimen.

Extended release: Oral: 2 g twice daily as part of an appropriate combination regimen.

• Rhinosinusitis, acute bacterial

Standard dose: Oral: Immediate release: 500 mg every 8 hours or 875 mg every 12 hours for 5 to 7 days.

High dose: Oral: Extended release: 2 g every 12 hours for 5 to 7 days.

• Streptococcus, chronic carriage

Oral: Immediate release: 40 mg/kg/day in divided doses (eg, 875 mg every 12 hours) (maximum: 2 g/day) for 10 days.

• Urinary tract infection

Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract, prostate, or systemic infection) : Oral: Immediate release: 500 mg twice daily for 5 to 7 days.

Urinary tract infection, complicated (including pyelonephritis) : Oral: Immediate release: 875 mg twice daily for 10 to 14 days; for patients with symptomatic improvement within the first 48 to 72 hours of therapy, some experts recommend shorter courses of 7 to 10 days.

Pediatric Dose

• Impetigo

Infants, Children, and Adolescents

Oral: 25 mg amoxicillin/kg/day in divided doses twice daily; maximum dose: 875 mg amoxicillin/dose.

• Pneumonia, community-acquired

Infants ≥3 months, Children, and Adolescents:

Oral: 90 mg amoxicillin/kg/day in divided doses twice daily; maximum daily dose: 4,000 mg/day.

• Rhinosinusitis, acute bacterial

Infants ≥3 months: Oral: 45 mg amoxicillin/kg/day divided every 12 hours, or 40 mg/kg/day divided every 8 hours.

Children and Adolescents: Oral:

Standard-dose regimen: 45 mg amoxicillin/kg/day divided every 12 hours for 10 to 14 days; usual adult dose: 875 mg amoxicillin/dose.

High-dose regimen: 80 to 90 mg amoxicillin/kg/day divided every 12 hours; maximum dose: 2,000 mg/dose; treatment duration variable: 10 to 28 days, some have suggested discontinuation of therapy 7 days after resolution of signs and symptoms of infection; some experts recommend a duration of 10 to 14 days.

• Streptococcus, group A; chronic carriage

Children and Adolescents: Oral: 40 mg amoxicillin/kg/day in divided doses every 8 hours for 10 days; maximum daily dose: 2,000 mg amoxicillin/day.

• Urinary tract infections

Infants ≥2 months and Children ≤2 years

Oral: 20 to 40 mg amoxicillin/kg/day in divided doses 3 times daily.

Amoxicillin + clavulanic acid is available in various strengths as 200 mg-28.5 mg; 400 mg-57 mg; 125 mg-31.25 mg; 250 mg-62.5 mg; 250 mg-125 mg; 500 mg-125 mg; 125 mg-31.25 mg/5 mL; 875 mg-125 mg; 200 mg-28.5 mg/5 mL; 250 mg-62.5 mg/5 mL; 400 mg-57 mg/5 mL; 600 mg-42.9 mg/5 mL; 1000 mg-62.5 mg.

Amoxicillin + clavulanic acid is available in the form of Oral tablet and Reconstituted Suspension. 

• Dosage Adjustment in Kidney Patient

Oral:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl 10 to <30 mL/minute: 250 to 500 mg every 12 hours.

CrCl <10 mL/minute: 250 to 500 mg every 12 to 24 hours.

IV:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 30 mL/minute: Initial: 1 g followed by 500 mg every 12 hours.

CrCl <10 mL/minute: Initial: 1 g followed by 500 mg every 12 to 24 hours.

Avoid consumption of hat-fat meal, as it may decrease absorption of clavulanic acid.

Amoxicillin + clavulanic acid is contraindicated in patients with

• Serious Hypersensitivity Reactions

Amoxicillin + clavulanic acid is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

• Cholestatic Jaundice/Hepatic Dysfunction

Amoxicillin + clavulanic acid is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Amoxicillin + clavulanic acid.

• Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including Amoxicillin + clavulanic acid. These Amoxicillin + clavulanic acid PLR Master 8 reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with Amoxicillin + clavulanic acid careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, Amoxicillin + clavulanic acid should be discontinued, and appropriate therapy instituted.

• Hepatic Dysfunction

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of Amoxicillin + clavulanic acid. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

• Clostridium difficile Associated Diarrhea (CDAD)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Amoxicillin + clavulanic acid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

• Skin Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, Amoxicillin + clavulanic acid should not be administered to patients with mononucleosis.

• Potential for Microbial Overgrowth

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

• Phenylketonurics

Amoxicillin + clavulanic acid Chewable tablets and Amoxicillin + clavulanic acid Powder for Oral Solution contain aspartame which contains phenylalanine. Each 200-mg chewable tablet of Amoxicillin + clavulanic acid contains 2.1 mg phenylalanine; each 400-mg chewable tablet contains 4.2 mg phenylalanine; each 5 mL of either the 200 mg/5 mL or 400 mg/5 mL oral suspension contains 7 mg phenylalanine. The other formulations of Amoxicillin + clavulanic acid does not contain phenylalanine.

• Development of Drug-Resistant Bacteria

Prescribing Amoxicillin + clavulanic acid in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Amoxicillin has been shown to be excreted in human milk. Amoxicillin and clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman.

Teratogenic Effects: Pregnancy Category B.

Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin : clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Common

Diarrhea, Candidal diaper rash, diaper rash, skin rash, urticaria, Nausea, vomiting, Vaginal mycosis, vaginitis, Candidiasis.

• Rare

Abdominal distress, flatulence, Thrombocytosis, Headache.

Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with Amoxicillin + clavulanic acid may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.

Oral Anticoagulants

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with Amoxicillin + clavulanic acid. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

Allopurinol

The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

Oral Contraceptives Amoxicillin + clavulanic acid may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

Effects on Laboratory Tests

High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with Amoxicillin + clavulanic acid, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

The common side effects of Amoxicillin + clavulanic acid include the following

• Common side effects

Diarrhea, upset stomach, vomiting, mild skin rash.

• Rare side effects

Severe skin rash, itching, hives, difficulty breathing or swallowing, wheezing, vaginal itching and discharge, yellowing of the skin or eyes.

• Pregnancy

Pregnancy Category B

Teratogenic Effects

Reproduction studies performed in pregnant rats and mice given Amoxicillin + clavulanic acid (2:1 ratio formulation of amoxicillin: clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin + clavulanic acid. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman.

• Pediatric Use

The safety and effectiveness of Amoxicillin + clavulanic acid Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Use of Amoxicillin + clavulanic acid in pediatric patients is supported by evidence from studies of Amoxicillin + clavulanic acid Tablets in adults with additional data from a study of Amoxicillin + clavulanic acid Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media. Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of Amoxicillin + clavulanic acid should be modified in pediatric patients aged <12 weeks (<3 months).

• Geriatric Use

Of the 3,119 patients in an analysis of clinical studies of Amoxicillin + clavulanic acid, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Symptoms: Gastrointestinal effects (e.g. stomach or abdominal pain, vomiting, and diarrhoea), rash, hyperactivity, drowsiness, fluid and electrolyte imbalance, crystalluria resulting in renal failure, and convulsions (in patients with renal impairment).

Management: Symptomatic and supportive treatment. Focus on water/electrolyte balance.

Pharmacodynamic

Amoxicillin, a semi-synthetic penicillin, inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins (PBPs), thereby blocking the final transpeptidation step of peptidoglycan synthesis in the bacterial cell walls. It is susceptible to degradation by β-lactamases which are produced by certain resistant bacteria.

Clavulanic acid, a β-lactam structurally related to penicillin, binds, and inhibits β-lactamases, thereby preventing amoxicillin inactivation and expands the amoxicillin spectrum of activity. It does not exert clinically significant antibacterial effect alone.

Pharmacokinetics

• Absorption

Amoxicillin: It is rapidly and well absorbed from the gastrointestinal tract. Increased absorption and decreased gastrointestinal upset with food. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1-2 hours.

Clavulanic acid: It is rapidly and well absorbed from the gastrointestinal tract. Decreased absorption with high-fat meals. The Bioavailability is approximately 70%. The Time to peak plasma concentration is about 1.5 hours.

• Distribution

Amoxicillin: Via IV, Amoxicillin readily distributed into body tissues and fluids (e.g. gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus) except the brain and CSF. It crosses placenta and enters breast milk. The Volume of distribution is approximately 0.3-0.4 L/kg. The Plasma protein binding is approximately 18%.

Clavulanic acid: Via IV, Clavulanic acid is well distributed into body tissues and fluids (e.g., gall bladder, abdominal or muscle tissues, skin, fat, synovial and peritoneal fluids, bile, pus). Crosses placenta and enters breast milk. Volume of distribution: Approx 0.2 L/kg. Plasma protein binding: Approx 25%.

• Metabolism

Amoxicillin: Metabolized to a limited extent to form inactive penicilloic acid.

Clavulanic acid: It is extensively metabolized.

• Excretion

Amoxicillin: It is excreted mainly via urine (approx 60-80% as unchanged drug). The Elimination half-life is approximately 1.3 hours.

Clavulanic acid: It is excreted via urine (approx 25-40% as unchanged drug); faeces; expired air. The Elimination half-life is approximately 1 hour.

Therapeutic benefits of Amoxicillin + clavulanic acid Combination

Amoxicillin + clavulanic acid is a combination of Amoxicillin and Clavulanic acid. Amoxicillin + clavulanic acid belongs to the group of medicines called antibiotics. Amoxicillin + clavulanic acid is used to treat bacterial infections of the ear, nose, throat, skin, bone, soft tissue, joints, urinary tract, and respiratory tract. Amoxicillin works by preventing the formation of bacterial cell covering, which is necessary for the survival of the bacteria. Thereby, kills the bacteria. Clavulanic acid works by decreasing bacterial resistance and enhancing the activity of amoxicillin against the bacteria. Together, Amoxicillin + clavulanic acid helps in treating bacterial infections. Amoxicillin + clavulanic acid is a broad-spectrum antibiotic that is effective against both gram-positive and gram-negative bacteria.

Amoxicillin + clavulanic acid is a combination of Amoxicillin and Clavulanic acid. Amoxicillin works by preventing the formation of bacterial cell covering, which is necessary for the survival of the bacteria. Thereby, it kills the bacteria. Clavulanic acid works by decreasing bacterial resistance and enhancing the activity of amoxicillin against the bacteria. Together, Amoxicillin + clavulanic acid helps in treating bacterial infections.

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• https://www.uptodate.com/contents/amoxicillin-and-clavulanate-drug-information#F134578
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050564s049,050720s022lbl.pdf
• https://www.drugs.com/pro/amoxicillin-and-clavulanate-tablets.html#s-43678-2
• https://medlineplus.gov/druginfo/meds/a685024.html#side-effects
• https://www.mims.com/malaysia/drug/info/amoxicillin + clavulanic acid?mtype=generic